ISSN 0100-879X

Volume 45 (9) 792-874 September 2012

CLINICAL INVESTIGATION

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Braz J Med Biol Res, September 2012, Volume 45(9) 792-798

doi: 10.1590/S0100-879X2012007500110

Pain-related diseases and sleep disordes

M. Roizenblatt, N.S. Rosa Neto, S. Tufik and S. Roizenblatt

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Brazilian Journal of Medical and Biological Research (2012) 45: 792-798

ISSN 0100-879X
Review

Pain-related diseases and sleep disorders

M. Roizenblatt1, N.S. Rosa Neto2, S. Tufik1 and S. Roizenblatt1
1Departamento

de Psicobiologia, Escola Paulista de Medicina,

Universidade Federal de So Paulo, So Paulo, SP, Brasil
2Centro de Dor e Neurocirurgia Funcional, Hospital Nove de Julho, So Paulo, SP, Brasil

Abstract
Pain and sleep share mutual relations under the influence of cognitive and neuroendocrine changes. Sleep is an important
homeostatic feature and, when impaired, contributes to the development or worsening of pain-related diseases. The aim of the
present review is to provide a panoramic view for the generalist physician on sleep disorders that occur in pain-related diseases
within the field of Internal Medicine, such as rheumatic diseases, acute coronary syndrome, digestive diseases, cancer, and
headache.
Key words: Sleep disorders; Rheumatic diseases; Acute coronary syndrome; Irritable bowel syndrome; Cancer; Headache

Introduction
Pain and sleep influence one another. Pain may be
exacerbated by sleep disorders (1) while sleep is impaired
by pain (2). The concept of pain-on and pain-off neurons
may explain the anatomical interactions of pain and sleep
phenomena. These neurons, which are situated in the
nucleus raphe magnus, respectively facilitate and inhibit
nociceptive impulses to thalamocortical pathways and
are influenced by the wake-sleep cycle: inhibitory pain-off
nerve cells are completely activated during deep sleep
while excitatory pain-on nerve cells are activated during
wakefulness (3). In this context, serotonin plays a role in
promoting both analgesia and deep sleep (4).
Neuroendocrine and autonomic mechanisms may
influence and be influenced by pain and sleep. Concerning chronic widespread pain syndromes, sleep disorders
and nociceptive afference are important to elevate the
sympathetic tonus, which my lead to vascular remodeling,
muscular atrophy and fatigue (5).
Pain and sleep disturbances may generate or perpetuate
cognitive, affective and motivational dysfunctions, which,
in turn, promote hypervigilance and frequent awakenings.
This is explained by the sharing of common afferent circuits
such as the parabrachial-amygdala and parabrachialhypothalamic pathways (6).
Less than 6 h of sleep may contribute to pain manifestations the following day (7). Similarly, sleep deprivation,
especially of deep sleep, results in wakening unrefreshed
with widespread pain and fatigue in healthy sedentary

individuals. In this context, alpha wave (8-10 Hz) activity

inappropriately intrudes during delta wave (0.5-3.5 Hz)
activity (8-10).
The restoration of adequate sleep is essential to avoid
exacerbation of painful symptoms (11). In the case of REM
sleep deprivation, a reduced pain threshold persists for a
variable period of time, even after normal sleep has been
restored (12).

Rheumatic diseases
Sleep disorders have been described in more than
75% of subjects suffering from various forms of rheumatic
diseases and fatigue is observed in up to 98% of cases
(13). Modifications of pain mediators, such as serotonin
and substance P, and of neuroimmune mechanisms, such
as inflammatory cytokines (interleukin-1 and tumor necrosis
factor-, TNF-) and cell-mediated immunity have been also
described. Moreover, there is the involvement of neuroendocrine mechanisms, such as the hypothalamic-pituitaryadrenal axis and the thyroid, alongside the autonomic
nervous system (13).
In general, there is reduced sleep efficiency accompanied by increased periods of wakefulness during the night.
Sleep is typically superficial and disrupted and primary sleep
disorders are frequent in these conditions, such as periodic
limb movements and sleep apnea (14).
Pain, sleep disturbance and depression are predictors

Correspondence: S. Roizenblatt, Av. Anglica, 1996, Conjunto 101, 01228-200 So Paulo, SP, Brasil. Fax: +55-11-3666-7484.
E-mail: suely.roizenblatt@unifesp.br
Received March 13, 2012. Accepted June 25, 2012. Available online July 6, 2012. Published August 17, 2012.
Braz J Med Biol Res 45(9) 2012

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Pain-related diseases and sleep disorders

793

of the severe fatigue that occurs in rheumatoid arthritis,

osteoarthritis, and fibromyalgia (15). The relationship between pain and sleep disorders in rheumatic diseases has
been observed not only in fibromyalgia (16) and rheumatoid
arthritis (15), but also in low back pain (17), osteoarthritis
(18), ankylosing spondylitis (19), Sjgrens syndrome (20),
systemic lupus erythematosus (21), systemic sclerosis (22),
and soft-tissue disorders (23).

lumbar spine (17), knee or hip (18) can impair sleep onset
and maintenance. The findings of sleep fragmentation due
to increased number of arousals (35) and periodic limb
movements (36) may explain fatigue and joint stiffness (of
less than 30 min) upon awakening, which are frequently
reported by the patients.

Fibromyalgia

Sleep studies are only available for carpal tunnel

syndrome. Patients may complain of nocturnal and early
morning awakenings with hand pain and numbness. Nonrestorative sleep, daytime sleepiness and polysonographic
findings such as arousals and periodic limb movement
indexes tend to improve after surgical treatment of the
affected wrist (23). However, carpal tunnel syndrome may
be the presenting symptom of underlying diabetes mellitus,
hypothyroidism or connective tissue disease, which are also
associated with sleep disorders.
Many investigators have tried to explain why tendonitis,
tenosynovitis, bursitis, and periarthritis tend to worsen at
night, as described for shoulder-related disorders, but the
reasons are still unclear and deserve more study (37).

The importance of non-restorative sleep, which affects

more than 90% of patients, is such that this manifestation
is now included among the new diagnostic criteria (24).
The non-restorative sleep and increased wake time after
sleep onset act as predictors of pain and fatigue and have
social implications, even when anxiety and depression are
excluded (25).
An electroencephalographic pattern of alpha wave
intrusion in delta wave sleep (alpha-delta sleep) has been
described in fibromyalgia (16), but also in other chronic
widespread pain conditions, and even in healthy individuals.
The phasic alpha-delta pattern, in which the distribution of
alpha activity overlaps the delta activity, especially during
slow-wave sleep (26), suggests that there is a disturbance
in fibromyalgia sleep homeostasis mediated by pain stimuli
that lead to awakening (27); however, studies have included
a small sample size of patients. Other authors focused on
the cyclic alternating pattern of non-REM sleep to explain
the relationship of altered sleep and pain perception (28)
and some controversial studies have reported reduction in
total sleep time and in sleep efficiency and modification of
sleep stage distribution, with a predominance of light sleep
compared to deep sleep, instead of sleep instability (29).
Changes in heart rate variability have also been described in patients with fibromyalgia, reflecting sympathetic
hyperactivity in contrast to hyporesponsiveness against
sympathetic stimulation, or during sleep (30).
A higher prevalence of upper airway resistance syndrome in patients with fibromyalgia (31) may not reflect a
direct relationship between the two conditions, since musculoskeletal pain may be attributed to restricted physical
activity in obstructive sleep apnea (32).
The approval of Pregabaline, a derivative of -aminobutyric
acid (GABA) that has analgesic, anticonvulsant, anxiolytic,
and sleep-modulating activities, has been a real advance
for the management of non-restorative sleep in fibromyalgia
(33), and odium oxybate, a metabolite of dopamine, which
increases GABA, has recently been proposed to increase
slow-wave sleep and decrease sleep disruption (34).

Osteoarthritis
Clinical symptoms of osteoarthritis tend to be exacerbated at night and on awakening. The involvement of the
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Soft tissue disorders

Ankylosing spondylitis
Up to 80% of patients with ankylosing spondylitis tend
to wake during the night in need of walking in order to get
some relief of low back pain. Polysomnography shows
increased sleep latency and fragmented sleep (19), which
can be the result of functional, often motor, disabilities.
Fatigue is a prominent symptom of ankylosing spondylitis,
reported by more than half the patients, and is associated
with functional disability (38). Also, patients complain about
excessive daytime sleepiness and the frequent need for
naps (39). Arthritis, costochondral inflammation and enthesitis gradually lead to spine ankylosis and chest wall
rigidity and obstructive sleep apnea, when present, further
aggravates the respiratory condition of the patients (40).
Anti-TNF agents improve both sleep disorders and inflammatory activity and shed light on the pathophysiology of
the disease (41).

Rheumatoid arthritis
Morning stiffness differs from osteoarthritis because
in rheumatoid arthritis it lasts more than 1 h and in osteoarthritis, less than 30 min (42). Additionally, association
between clinical manifestations of the disease and fatigue,
excessive daytime sleepiness and sleep alterations has
been reported (43). Decreased sleep efficiency, superficial
sleep, reduction in REM sleep, and an increase in the number of arousals (44) may exacerbate sleep fragmentation
and fatigue, as well as periodic limb movements (45) and
sleep apnea (46). Skeletal abnormalities, particularly of
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the temporomandibular joint and the cervical spine may

underlie sleep apnea in rheumatoid arthritis (47). As reported
in ankylosing spondylitis, improvement of the sleep apnea
and the fatigue following administration of TNF- blockers
has been demonstrated (48).

Sjgrens syndrome
Prominent fatigue is very commonly reported by patients and is related to sleep disorders, musculoskeletal
pain, anxiety (49), and fibromyalgia, which occurs in 55%
of the patients (50). Polysomnographic findings reflect the
non-restorative sleep condition reported by the patients,
with reduction in sleep efficiency, intermediate awakenings (20) and rhythmic oral movements attributed to the
lack of saliva (51).

Systemic lupus erythematosus

Besides prominent fatigue that is the hallmark of rheumatic diseases with a remarkable autoimmune component
(21), and polysomnography findings of increased sleep
latency and reduced total sleep time, not related to depression (52), co-morbidities play an important role in pain and
sleep interactions in systemic lupus erythematosus. Obesity,
neuropsychiatric and kidney involvement and the use of
medications such as antihistamines and glucocorticoids
may act as confounders when restless legs syndrome (53)
and sleep apnea (54) are present.

Scleroderma
Fatigue and poor sleep are also frequent complaints
in scleroderma (55). In addition, sleep disturbances may
aggravate the manifestations of the disease. The presence
of sleep apnea may contribute to endothelial damage,
particularly in the lungs, periodic limb movements may aggravate nocturnal pain due to ischemia and the presence of
gastroesophageal reflux may contribute to the fragmentation
of sleep and fatigue (22).

Coronary heart disease

Among the changes in sleep architecture in acute
coronary syndromes, the most frequent are difficulty of
initiating and maintaining sleep, the presence of arousals
and reduced total sleep time. It has been hypothesized that
both quantity and quality of sleep have a negative influence
on patient recovery (56). Superficial and disrupted sleep is
described in 60% of patients with coronary artery disease
and is compared to the hypervigilance observed in posttraumatic stress disorder (57).
Sleep disorders in patients with coronary artery diseases
may aggravate myocardial ischemia. Given that cytokines
modulate sleep, an immune substrate has been considered
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to explain insomnia and parasomnias, such as nightmares,

which may precede an acute coronary syndrome. Moreover,
hypoxemia due to obstructive sleep apnea, when present,
promotes the deterioration of cardiac ischemia (58).

Digestive tract diseases

Irritable bowel syndrome
Complaints of abdominal cramps and flatulence persist
during the night, awakening the patient. Sleep fragmentation
leads to poor sleep, which, in turn, promotes deterioration of
intestinal symptoms (59). In addition, patients have altered
perception of their sleep, considering that it has not been
established that sleep latency or efficiency are altered in
irritable bowel syndrome (60). Autonomic dysfunction, in
terms of increased sympathetic tonus during REM sleep,
may underlie the relationship between disease activity and
sleep fragmentation (61).
Gastroesophageal reflux disease
Although the frequency of gastroesophageal reflux is
highest during wakefulness, its presence during sleep has
a greater impact on the quality of life of the patients. This
is because night reflux lasts longer and saliva production
is reduced. In addition to the sleep fragmentation and early
awakening, gastroesophageal reflux causes respiratory
symptoms such as coughing and wheezing. Aspiration of
gastric acid reflux into the larynx is common in individuals
with asthma (62). The stimulation of vagal nerve afferents
in the distal esophagus by the presence of gastric acid
reflux supports the treatment of the disease when present
in asthma patients. Lifestyle modifications and eating light
meals at night at least 2 h before bedtime, are advised even
when there is indication for surgery. Additionally, raising
the head of the bed and sleeping in left lateral position are
recommended in order to reduce esophageal acid exposure
and to increase esophageal clearance of gastric contents.
The association of proton pump inhibitors helps improve
sleep quality (63).

Neoplastic diseases
The combination of pain, fatigue and sleep disturbances
is reported by more than 40% of cancer patients (64). Pain
occurs in 59% of individuals under treatment for cancer
and 64% of those with advanced disease (65). Fatigue
affects most patients, especially after surgical procedures,
chemotherapy, immunotherapy and radiotherapy. Fatigue,
excessive sleepiness and restless legs syndrome may all
be associated with anemia and iron deficiency and occur
particularly in lung, breast, genitourinary, gastrointestinal,
and non-melanoma skin cancer (66).
Besides fragmented and superficial sleep, reported in
up to 72% of the cases (67), screening for the presence of
sleep apnea is appropriate in patients with oral or oropharynx
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Pain-related diseases and sleep disorders

cancer before and after treatment (68).

Treatment of insomnia may improve fatigue and even
immunity in cancer patients. However, sedatives and sleep
inducers may result in lack of attention or drowsiness during
the day, which could enhance fatigue and muscle pain and
reduce the pain threshold (69). Moreover, pain killers and
steroids may aggravate the symptoms of fatigue, increase
daytime sleep and worsen non-restorative sleep (70), and
opioids may contribute to the emergence of central apnea
during sleep (71). In addition, side effects of chemotherapy,
pain, nausea, diarrhea, and urinary urgency facilitate sleep
fragmentation (68). Such interruptions invariably result in
insufficient rest and increased fatigue. It is worth noting the
value of behavioral psychological intervention that improves
sleep quality and cancer-related fatigue (72).

Headaches
There is a strong interface between sleep disorders and
headaches. Even though a causal link between the two
conditions has not yet been established, improvement in
sleep quality results in improvement of headache, especially
in cases of sleep deprivation (73).
The relationship between sleep-wake cycle and the various types of headaches, such as migraine, cluster headache
and paroxysmal hemicrania, is due to the activation of the
posterior hypothalamus. Brain stem and diencephalon
pathways in headaches are related to sleep fragmentation,
as also described for visceral pain (74).
Sleep disorders are found in patients with morning or
night occurring migraine. The circadian periodicity in morning migraine is related to REM sleep and glucocorticoids
and catecholamine cycles (73). Night migraine, in turn, may
involve alterations in the regulatory mechanisms of awakenings during sleep. Crises tend to be preceded by episodes
of yawning. Despite the fragmented sleep during periods of
crises, fewer awakenings have been described in the night
preceding the night migraine episodes (75).
Cluster headaches tend to predominate in the early
morning hours and 90 min after sleep onset. The substrate
of their association with REM sleep is secretion of melatonin
and cortisol (76). Paroxysmal hemicrania also has a certain
relation to REM sleep (77). In contrast, hypnic headache
tends to awaken the patient in the first half of the night for
at least 15 nights a month. Interestingly, treatment of sleep
fragmentation tends to improve chronic migraine, tension
headache, cluster headache, and hypnic headache pain
intensity (78). Insomnia and nonrestorative sleep have
been recognized as risk factors for chronification of tension
headache, migraine and medication overuse headache
(79) and restoration of sleep quality, in turn, reverses the

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795

condition (80).
A possible link between primary headaches and narcolepsy has been proposed to be due to a higher frequency of
migraine in patients with narcolepsy, especially in women,
which may experience episodes of narcolepsy prior to the
migrainous attacks (81). The polymorphism of receptor-2 of
the gene encoding orexin/hypocretin, which is involved in
the sleep-wake cycle in narcolepsy and in pain modulation,
has been described in individuals with cluster headaches
(82). It is, therefore, evident that the damage of lateral
hypothalamic orexinergic neurons affects the activation of
REM-off neurons that disrupt REM sleep. These neurons
in the ventrolateral periaqueductal gray substance are
also involved in the reduction of nociceptive activity in the
trigeminal and caudate nucleus and their inhibition favors
pain mechanisms (81).
The correlation between severity of migraine and the
presence of restless legs syndrome may demonstrate that
migraine may also have a substrate of dopaminergic impairment (83), iron metabolism imbalance (84) and depression
(85), as occurs in restless legs syndrome.
In morning and night migraine, 30-70% of patients have
obstructive sleep apnea or intense snoring (86). Cluster
headache and paroxysmal hemicranic headache, particularly in its chronic form, are also more frequent in subjects
with obstructive sleep apnea than in the general population (87). Conversely, 15-74% of patients with obstructive
sleep apnea wake up with headache, and in 48% of cases
the headache pattern cannot be classified (88). Nocturnal
awakenings accompanied by intense headache crises in
individuals with obstructive sleep apnea have been associated with intracranial hypertension (89).
Possible pathophysiological bases for the association
between headache and sleep apnea are hypoxemia and
hypercapnia, since symptoms improved after treatment with
continuous positive airway pressure (CPAP) or supplemental oxygen (88). Morning migraine related to sleep apnea is
more prevalent in women with moderate to severe apnea
and in subjects with a history of primary headache, and
tends to improve with the use of CPAP (90). Likewise, the
benefit of CPAP is observed in cluster headaches triggered
by oxyhemoglobin desaturation, especially during REM
sleep (87).

Conclusion
The generalist physician should be aware of the contribution of sleep to the initiation or worsening of diseases that
have pain as a prominent manifestation. Further reviews
are warranted to discuss the pathophysiology underlying
such association.

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